Publication Date
2023
Document Type
Dissertation
Committee Members
Keiichiro Susuki, M.D., Ph.D. (Advisor); Mark Rich, M.D., Ph.D. (Committee Member); Clintoria Williams, Ph.D. (Committee Member); Michael Hennessy, Ph.D. (Committee Member); Lynn Hartzler, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Dementia and mild cognitive impairment are well recognized comorbidities of type 2 diabetes, termed diabetic encephalopathy, that lack in course modifying treatment options. The axon initial segment (AIS) is a critical mediator of neuronal output. Shortening of AIS length has been shown to decrease neuronal excitability and is implicated in diabetic encephalopathy. AIS shortening may be reversible, hence investigating the mechanism responsible could address this significant gap in patient care by providing new therapeutic targets. Endoplasmic reticulum (ER) stress, a cellular condition that activates the unfolded protein response has been implicated in diabetic encephalopathy. Here, using immunocytochemistry in primary mouse cortical neuron culture, we demonstrate that inhibition of ER stress prevents AIS shortening induced by the type 2 diabetic factor methylglyoxal, and induction of ER stress leads to AIS shortening. These results suggest that ER stress is necessary and sufficient for AIS shortening in diabetic conditions. Furthermore, we present changes in AIS morphology and cognitive performance after pharmacological inhibition of ER stress in db/db mice, an established model of type 2 diabetes. These findings identify ER stress and AIS shortening as potential therapeutic targets to mitigate cognitive impairment in diabetic encephalopathy.
Page Count
93
Department or Program
Biomedical Sciences
Year Degree Awarded
2023
Copyright
Copyright 2023, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0002-4746-3876
